In 2005, there were an estimated 18,500 new cases of brain tumors and estimated 12,760 deaths. Gliomas are the most common primary tumors arising from the central nervous system and of the gliomas the most common form (and the most aggressive) is glioblastoma multiforme. At present with surgery, chemotherapy and radiation the survival of the most aggressive of the primary tumors of the brain, i.e., glioblastoma multiforme (WHO grade IV) is only 50 weeks. Less than 2% of patients survive three years post diagnosis. Less than 30% of malignant gliomas respond to adjunct chemotherapy. The epidermal growth factor receptor is frequently overexpressed or mutated in glioblastomas, but only 10 to 20% respond to epidermal growth factor receptor kinase inhibitors. It is important to note in this regard that the “response” referred to above was not that the tumor was eliminated or decreased in volume but rather that the tumor did not grow more than 25%. In each of the “response” patients the glioblastomas began to grow again in approximately three months.
Cardiac natriuretic hormones are a family of peptide hormones that have significant anticancer effects on human prostate, breast, colon, and pancreatic adenocarcinoma cells (see Vesely, B. A., McAfee, Q., Gower, W. R., Jr., and Vesely, D. L. (2003) Four peptides decrease the number of human pancreatic adenocarcinoma cells. Eur. J. Clin. Invest. 33, 998-1005; Vesely, B. A., Alli, A. A., Song, S., Gower, W. R., Jr., Sanchez-Ramos, J., and Vesely, D. L. (2005a) Four peptide hormones specific decrease (up to 97%) of human prostate carcinoma cells. Eur. J. Clin. Invest. 35, 700-710; Vesely, B. A., Song, S., Sanchez-Ramos, J., Fitz, S. R., Solivan, S. M., Gower, W. R., Jr., and Vesely, D. L. (2005c) Four peptide hormones decrease the number of human breast adenocarcinoma cells. Eur. J. Clin. Invest. 35, 60-69; and Gower, W. R., Jr., Vesely, B. A., Alli, A. A., and Vesely, D. L. (2005) Four peptides decrease human colon adenocarcinoma cell number and DNA synthesis via guanosine 3′, 5′-cyclic monophosphate. Int J Gastrointestinal Cancer 36, 77-88; which are incorporated herein by reference) as well as upon small-cell and squamous lung carcinoma cells in vitro (see Vesely B. A., Song S., Sanchez-Ramos J., Fitz S. R., Alli A. A., Solivan S. M., Gower W. R. Jr., and Vesely D. L. (2005) Five cardiac hormones decrease the number of human small-cell lung cancer cells. Eur. J. Clin. Invest. 35, 388-398; Vesely, B. A., Fitz, S. R., Gower, W. R., Jr., and Vesely, D. L. (2006) Vessel dilator: Most potent of the atrial natriuretic peptides in decreasing the number and DNA synthesis of squamous lung cancer cells. Cancer Lett. 232, 226-231, which are incorporated herein by reference).
Of this family of peptide hormones, one gene in the heart synthesizes a 126 amino acid (a.a.) prohormone which with proteolytic processing results in four peptide hormones consisting of 1) the first 30 a.a. of this prohormone (i.e., long acting natriuretic peptide, LANP), 2) vessel dilator (VDL, a.a. 31-67), 3) kaliuretic peptide (KP, a.a. 79-98), and 4) atrial natriuretic peptide (ANP, a.a. 99-126) of the 126 a.a. prohormone (FIG. 1). Vessel dilator appears to have the strongest anticancer effects decreasing up to 97% the number of human prostate and colon cancer cells within 24 hours. In vivo, vessel dilator decreases the volume of human pancreatic adenocarcinomas growing in athymic mice the most (49% decrease in tumor volume in one week), while all four peptide hormones stop the growth of this cancer in vivo. None of these cardiac hormones have ever been investigated on any tumor in the brain i.e., in the central nervous system. The four peptide hormones synthesized by the cardiac gene were evaluated for their effects on the most common of the central nervous system tumors, i.e., glioblastomas. In addition, a peptide similar to ANP has been isolated from the venom of the Green Mamba snake and termed Dendroaspis Natriuretic Peptide (DNP; see Schweitz, H., Vigne, P., Moinier, D., Frelin, C., and Lazdunski, M. (1992) A new member of the natriuretic peptide family is present in the venom of the Green Mamba (Dendroaspis augusticeps, J. Biol. Chem. 267, 13928-13932, which is incorporated herein by reference).